Molecule mimics naturally occurring protein to prevent overreaction
SAN DIEGO—Sometimes an immune response can do more harm than good. Researchers at the University of California, San Diego’s School of Medicine discovered that a molecule called Girdin, or GIV, acts as a brake on macrophages, immune cells that detect pathogens and start an inflammatory response as needed.
A study published in October in the Proceedings of the National Academy of Sciences revealed that a synthetic peptide can keep the macrophages from causing damage to the body when fighting off offending bacteria or viruses. Funding for this research came, in part, from the National Institutes for Health.
“When a patient dies of sepsis, he or she does not die due to the invading bacteria themselves, but from an overreaction of their immune system to the bacteria,” explained senior author Dr. Pradipta Ghosh, a professor at UC San Diego School of Medicine and Moores Cancer Center. “It’s similar to what we’re seeing now with dangerous ‘cytokine storms’ that can result from infection with the novel coronavirus SARS-CoV-2.”
When the researchers removed the GIV gene from mouse macrophages, the immune cells quickly overacted to tiny amounts of live bacteria or a bacterial toxin. Mice that had colitis and sepsis were in a less-optimal condition when they lacked the GIV gene in their macrophages. Additionally, the team created peptides that mimic GIV, enabling the shutdown of mouse macrophages on command. Treatment with the GIV-mimic peptide tempered the mice’s inflammatory response.
According to Ghosh, “The GIV-mimic peptide is a tiny synthetic peptide that encodes the sequence naturally found in GIV. This sequence is what GIV uses to keep the TLR4 receptors apart so that the receptors do not fire inflammatory signaling cascades too early or too excessively.”
She added, “The tail end of GIV protein uses a small sequence to directly bind the tail end of TLR4 that is within the cell. This part of the receptor allows signals (bacteria and microbe antigens) from the outside to be relayed to the cell’s interior. But signals can only be relayed when two TLR4’s dimerize (couple with each other) after sensing such signal. Dimerization requires the tail ends of two receptors to bind to each other. That is the exact region where GIV binds. By binding to the TLR4 receptors, GIV can therefore inhibit dimerization and signaling. Basically, GIV inhibits the receptors from dimerizing and signaling.”
Upon sending microbes or microbial parts, the macrophages rapidly dial down levels of GIV, according to Ghosh. This is likely to enable inflammation, which results in immunity. However, after the threat has resolved and healing must begin, the macrophages dial back up the levels of GIV. Ghosh explained, “We have determined that both the mRNA and protein levels of GIV go up or down, indicating that this regulation is mediated, perhaps via transcriptional control and/or RNA stabilization. Who or what controls those processes is under investigation.”
The researchers plan to investigate the factors that determine how the GIV brake remains in place when macrophages are resting or removed to mount a response to a credible threat. The Institute for Network Medicine at UC San Diego School of Medicine recently received a new $5-million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, to engage in these studies. Ghosh and her team are sharing this award with her colleagues Dr. Debashis Sahoo, assistant professor at UC San Diego School of Medicine and Jacobs School of Engineering, and Dr. Soumita Das, associate professor of pathology at UC San Diego School of Medicine.
“We expect to find that factors that normally orchestrate the GIV-brake are vital for preventing an overreaction to any infection (credible threat),” Ghosh explained. “We expect to see that dysregulation of these factors may be associated with, for example, death during sepsis, or colitis, liver fibrosis and other conditions. We expect that these insights could be exploited to create peptidomimetic drugs that can allow us to dial down the level of inflammation. On the flip side, if the brake is not removed in a timely manner, we expect to see immune apathy, such as encountered in an immunosuppressed state.”